Identification of genes involved in early stage bladder pathogenesis

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Transitional cell carcinoma of the bladder (TCC) ranks 4th in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are few reliable diagnostic or prognostic tests for this disease, and biomarkers for early detection and prognosis remain evasive. We have interrogated the UPII-SV40T transgenic mouse model for invasive bladder cancer (Zhang et al, Cancer Res. 59:3512-3517, 1999) with DNA microarray technology to identify potential biomarkers for early detection and prognosis of TCC. We have identified genes that are differentially expressed between the bladders of UPII-SV40T mice and their age-matched wild type (WT) littermates at 3, 6, 20 and 30 weeks of age, which correspond to premalignant, carcinoma in-situ, and early and later stage TCC, respectively. We identified approximately 1,400 genes that are differentially expressed at the mRNA level (> 2-fold difference) between WT and UPII-SV40T urothelium at the 3-week time point. Bioinformatic pathway analysis revealed that a large proportion of the genes upregulated in the UPII-SV40T urothelium are cell cycle regulatory and cytokinesis genes, such as c-jun, cyclins B1, E2, A2 and F, Cdc7, Cdc2a, Cdc20, Cdc6, Cdca3, E2f8, Spbc24, Cenpf, Cenph, Top2a, and many others. Among the genes suppressed in the UPII-SV40T urothelium, a large proportion are structural and cell adhesion genes such as Col1a1, Col1a2, Col6a2, Col3a1, Tnc, Dmn, Vcam1, and uroplakin 2 itself. We are testing patient tissue and urine specimens for expression of several of the genes found to be upregulated in UPII-SV40T urothelium. Promising genes will be further studied as potential biomarkers for early stage primary or recurrent bladder TCC. Ultimately we seek to determine the molecular mechanisms involved in the pathogenesis of TCC.